rs4845394

Variant names:

• chr1-154835811-G-A
• rs4845394
• NM_002249.6:c.934-13627C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002249.6(KCNN3):​c.934-13627C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 152,118 control chromosomes in the GnomAD database, including 11,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11478 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 10 publications found

Genes affected

KCNN3 (HGNC:6292): (potassium calcium-activated channel subfamily N member 3) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

KCNN3 Gene-Disease associations (from GenCC):

• Zimmermann-Laband syndrome 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.934-13627C>T		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.934-13627C>T		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.-6-13627C>T		intron	N/A	NP_001352766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.934-13627C>T		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.19-13627C>T		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.-6-13627C>T		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57848 AN: 152000 Hom.: 11487 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.408

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.380 AC: 57840 AN: 152118 Hom.: 11478 Cov.: 32 AF XY: 0.380 AC XY: 28264 AN XY: 74362

African (AFR) AF: 0.263 AC: 10917 AN: 41494

American (AMR) AF: 0.465 AC: 7113 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1813 AN: 3468

East Asian (EAS) AF: 0.362 AC: 1870 AN: 5168

South Asian (SAS) AF: 0.379 AC: 1826 AN: 4818

European-Finnish (FIN) AF: 0.339 AC: 3589 AN: 10590

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29341 AN: 67970

Other (OTH) AF: 0.403 AC: 852 AN: 2114

Alfa AF: 0.431 Hom.: 26729

Bravo AF: 0.384

Asia WGS AF: 0.320 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.59
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4845394; hg19: chr1-154808287;